{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T04:52:07Z","timestamp":1785646327222,"version":"3.56.0"},"reference-count":41,"publisher":"American Society of Hematology","issue":"23","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,6,4]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>T-cell acute lymphoblastic leukemia (T-ALL) results from the malignant transformation of thymocytes blocked in their differentiation. Surface expression of the \u03b3\u03b4 T-cell receptor (\u03b3\u03b4TCR) is surprisingly frequent in T-ALLs, questioning the susceptibility of the \u03b3\u03b4-lineage to leukemogenesis. Among 1233 T-ALLs phenotyped in our center, 33% (n = 403) expressed a TCR, of which 47% (n = 191; 113 adults, 78 children) were positive for \u03b3\u03b4TCR (\u03b3\u03b4TCR+). Using a comprehensive analysis, we were able to delineate 2 distinct \u03b3\u03b4TCR+ T-ALL subtypes, with distinct physiological counterparts. The first (75% of cases) was characterized by ectopic expression of homeodomain-containing oncogenes (HD+), V\u03b2-J\u03b2 rearrangements, and phenotypic (including surface pre-TCR\u03b1 chain) and transcriptional profiles reminiscent of cortical thymocytes and was, therefore, termed cortical-like \u03b3\u03b4 T-ALLs. Transduction of murine T-cell progenitors and human CD34+ cells with HOXA9 or TLX3 (HD+ oncogenes) led to a differentiation bias toward \u03b3\u03b4TCR-expressing thymocytes. The second subtype (25%) exhibited phenotypic and transcriptional profiles reminiscent of \u03b3\u03b4 thymocytes, and was termed bona fide \u03b3\u03b4 T-ALLs. These findings were validated in the COGAALL0434 cohort. Although bona fide \u03b3\u03b4 T-ALLs were enriched for early T-cell progenitor (ETP)\u2013like and KMT2A-rearranged cases, they mostly eluded the phenotypic definition of ETP-ALLs. Similar to the ETP-like subtype, bona fide \u03b3\u03b4 T-ALLs were associated with a poor initial response to chemotherapy but were sensitive to the BCL2 inhibitor venetoclax. Our results reveal developmental heterogeneity behind \u03b3\u03b4TCR expression in T-ALLs and suggest that overrepresentation of this subtype reflects \u03b1\u03b2-lineage commitment repression by HD+ oncogenes. These trials were registered at www.clinicaltrials.gov as NCT00222027 (GRAALL2003), NCT00327678 (GRAALL2005), NCT03709719 (GRAALL2014), and NCT00408005 (Children's Oncology Group AALL0434 trial).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025030626","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T21:20:02Z","timestamp":1769548802000},"page":"2793-2808","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":2,"title":["Homeodomain-driven oncogenic diversion to a \u03b3\u03b4TCR phenotype in T-cell acute lymphoblastic leukemia"],"prefix":"10.1182","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2801-6824","authenticated-orcid":false,"given":"Antoine","family":"Pinton","sequence":"first","affiliation":[{"name":"1Institut Necker Enfants Malades, INSERM U1151, Centre National de la Recherche Scientifique Unit\u00e9 Mixte de Recherche 8253, Universit\u00e9 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